Sunitinib (Compound I) is the international commonly accepted name for N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, and has an empirical formula of C22H27FN4O2, and a molecular weight of 398.47. Sunitinib is an active pharmaceutical substance indicated for the treatment of abnormal cell growth, such as cancer, in mammals, particularly in humans.

The malate salt of sunitinib has been selected for medical purpose and is commercially marketed under the trade name of SUTENT™ for the treatment of renal cell carcinoma and gastrointestinal stromal tumors.
Sunitinib base and its malate salt are described in U.S. Pat. No. 6,573,293 (“the '293 patent”), which is incorporated herein by reference. In particular, Example 80 (Alternative Synthesis) of the '293 patent describes the preparation of sunitinib base via condensation of 5-fluoro-1,3-dihydroindol-2-one and N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide, in the presence of pyrrolidine and ethanol.
Applicants have prepared sunitinb base following the teachings of Example 80 (Alternative Synthesis) of the '293 patent (i.e., see Comparative Example 1 of the present invention) and the crystalline form of sunitinib base obtained, referred to herein as sunitinib base Form III, has been characterized herein by X-ray powder diffraction (XRD), infrared (IR) spectroscopy, and differential scanning calorimetry (DSC).
Applicants have observed that the sunitinib base obtained in the prior art (i.e., sunitinib base Form III) presents a low solubility profile, which makes dissolving sunitinib and the preparation of corresponding pharmaceutically acceptable salts troublesome. This observation is in accordance with the European Public Assessment Report provided for SUTENT™ which discloses that sunitinib is classified as a low solubility compound according to the biopharmaceutical classification. In this regard, the low solubility of sunitinib base Form III would involve the use of large amounts of suitable solvents or mixture of solvents and/or the use of particular conditions aimed to improve the solubility of sunitinib base Form III and/or long reaction times for processes using sunitinib, which may represent an important drawback, especially for processes on an industrial scale.
Furthermore, no other polymorph of sunitinib, other than sunitinib base Form III, is reported in the literature. Additionally, there is no crystal structure data in the literature for sunitinib base Form III.
Polymorphism is common among chemical substances and is commonly defined as the ability of a substance to exist in two or more crystalline phases that have a different arrangement and/or conformation of the molecules in the crystal lattice. Different polymorphs typically differ in their physical properties such as, for example, melting point, solubility, and chemical reactivity. Thus, the particular characteristics of the respective polymorphs can appreciably influence the solubility profile of a chemical substance. Further, the particular characteristics of the respective polymorphs can appreciably influence pharmaceutical properties such us dissolution rate and bioavailability.
Accordingly, there is a need to identify and isolate new polymorphic forms of sunitinib base, as well as to develop processes for producing sunitinib base in new polymorphic forms. In addition, there is a need for improved pharmaceutical compositions comprising sunitinib base in one or more polymorphic forms.